Endogenous opioids could represent a significant vasoactive component in the cerebral circulation. The opioids are intrinsic modulators of the cerebral circulation. I will test the hypothesis that opioids act on the cerebral circulation directly as well as indirectly by interacting with neural stimuli and prostanoids. To test these hypotheses, three specific aims will be addressed: 1) characterize the relationship between cerebral opioid concentrations and cerebral hemodynamics during control conditions and during a condition that changes cerebral vascular resistance, namely hemorrhagic hypotension; 2) determine the functional significance of the relationship between cerebral opioids and the cerebral circulation; and 3) investigate the mechanisms by which endogenous opioids affect cerebral hemodynamics by determining the interaction of opioids with other important vascular regulators such as the prostanoid, vasopressin, and adrenergic nervous systems. Both the "closed" cranial window and radiolabelled microspheres methods will be used in these experiments. Using the cranial window, the investigator can: 1) directly observe and measure diameters of cerebral resistance vessels, 2) perivascularly apply opioids and other drugs, and 3) sample cortical periarachnoid cerebrospinal fluid, and measure opioid, vasopressin, catecholamine, and prostanoid levels via HPLC and radioimmunoassay. To complement the window experiments, radiomicrospheres will be used to allow study of distribution of cerebral blood flow and cerebral oxygen consumption. This investigation will explore mechanisms involved in the regulation of the cerebral circulation during normal and pathologic conditions and will provide new information in an area where little data are available. These experimental findings may be of clinical relevance and lead to therapies that improve outcome in stressed individuals.